PROJECT SUMMARY Given the lack of effective treatments for Alzheimer?s disease (AD) and related dementias (ADRD), identification of modifiable risk factors is critical. Sensory impairments may affect over 50% of adults aged 65 years and older and have been linked to Alzheimer?s disease (AD) and related dementias (ADRD). However, the nature of this association in diverse aging populations is not well understood. Furthermore, the underlying pathways and mechanisms for why hearing and visual impairments predict dementia are unclear. Hearing and visual impairments are hypothesized to 1.) directly impact brain structure and function to accelerate cognitive decline, 2.) indirectly influence cognitive decline due to links to other dementia risk factors such as psychosocial factors, or 3.) represent underlying neurodegeneration or cardiovascular disease. The scientific goal of this study is to adopt a systematic approach to evaluate the role of hearing and visual impairments in cognitive decline and risk of dementia as well as to identify mechanisms that explain the relationship. This project focuses on hearing and visual impairments as these have the greatest effect on quality of life and high potential for treatment or correction. In a feasible and cost-effective approach, this project will leverage three existing and complementary studies of aging that have measures of sensory and cognitive function: The Health Aging and Body Composition Study, a 15-year population-based cohort of 3,075 black and white adults in the U.S; the National Alzheimer?s Coordinating Center, a database of US Alzheimer?s Disease Center participants including autopsy findings; and The UK Biobank, a study of 500,000 UK adults with clinical and genetic data. Innovative and rigorous epidemiologic approaches will be applied to conduct 1.) a study of diverse older adults using objective measures of hearing and visual impairments and 2.) a Mendelian Randomization analysis, a novel approach to enhance causal inference, as well as studies to determine whether associations are explained by 3.) underlying neuropathologic mechanisms or by 4.) psychosocial mediators. The research plan in this mentored career development award is complemented by training activities that build on the candidate?s background in epidemiology and provides new training in a.) clinical dementia assessment, b.) advanced casual inference methods, and c.) age-related hearing and visual impairments. Together the candidate?s research aims, training activities, and guidance from a multidisciplinary mentorship team will allow the candidate to develop a successful independent research program examining the relationship between sensory impairments and ADRD. The current research plan is expected to provide critical insight into what factors and mechanisms can explain the associations between sensory impairment and ADRD. These findings will inform whether sensory impairments or their downstream psychosocial effects can be used as targets for intervention to prevent dementia, or whether sensory impairments can be used as clinical predictors for identifying preclinical AD or cerebrovascular disease.